NCAM is a cell surface glycoprotein belonging to the Ig superfamily of CAMs (for review see Kiselyov et al., 2005). NCAM can be expressed as three major isoforms (A, B and C) with differences in the cytoplasmic domain. The extracellular part of NCAM is identical for the three isoforms and consists of five Ig-like and two fibronectin type III (F3) modules. NCAM is widely expressed during embryonic development, whereas in the adult organism it is mainly found in tissues of neural origin. NCAM plays a major role during development of the nervous system, mediating adhesion between neural cells and stimulating neurite outgrowth and fasciculation, promoting cell survival and synaptic plasticity (Cremer et al., 1997; Berezin et al., 2000; Bruses and Rutishauser, 2001; Rougon and Hobert, 2003; Walmod et al., 2004). NCAM mediates cell-cell adhesion through homophilic binding and regulates neurite outgrowth via FGFR (Doherty and Walsh, 1996; Kiselyov et al., 2003 and 2005). The FGFR site involved in binding to NCAM has been mapped to the Ig3 module, and the corresponding site in NCAM—to the second F3 module (Kiselyov et al., 2003). This interaction leads to activation of intracellular signaling cascades mediating cell differentiation and survival.
The identified NCAM fragment having the sequence EVYVVAENQQGKSKA (FGL peptide) involved in the direct interaction between NCAM and FGFR has recently been suggested as a new candidate compound for the treatment of a variety of pathologic disorders where the stimulation of activity of FGFR may play the key role (WO 03/016351). It is located in F3, II and binds and activates the FGF receptors 1 and 2, promotes neurotigenesis, and neuronal cell survival in vitro (Kiselyev et al., 2003; Neiiendam et al., 2004) and improves long-term memory in rat (Cambon et al., 2004). The FGL peptide has also been shown to promote neuronal survival and rescue the cognitive deficit in a rat model of amyloid-beta peptide induced neurotoxicity. (Klementiev et al. 2007).